Patients need transparency around how new medicines are approved
One of my most uncomfortable professional moments occurred some years ago when I cared for a successful business owner with advanced cancer. Following a stable period for years, her illness eventually entered a rapid trajectory when successive therapies began failing. It was around this time that I broached my concern that treatments were causing more harm than good, and the way to stop feeling so awful was by eschewing further toxic therapies in favour of symptom management.
With the help of an intuitive sister, she was beginning to come around to an acceptance of her mortality, which is why I was surprised to see her in the chemotherapy chair, supervised by a dejected nurse who told me the patient had been prescribed a “Hail Mary”. Hail Mary, a Christian utterance of holy intervention, crossed into the realm of oncology when pressured doctors began prescribing futile treatments to desperate patients.
The chemotherapy was known for its universally dismal response and propensity for complications, but each time I saw her from a distance I only felt the special humiliation of a doctor who has lost a patient in search of a better provider. Each week, she grew weaker and more jaundiced and yet, I thought I was the one in error.
One day I ran into her new oncologist.
“I completely agree with you,” he said. “She is dying.”
“Then why did you prescribe more treatment?”
“Because it was there.”
Three weeks later, the patient died. The personal toll of chemotherapy at the end of life was clear but the other cost was that of the invisible suffering endured by her family and the moral distress of the providers who witnessed her predictable downfall.
Memories of that patient came flooding back recently when I learnt that the US Food and Drug Administration (FDA) had approved a drug for dementia, a disease that is becoming emblematic of an ageing population.
The drug works by clearing amyloid from the brain although it is unclear whether amyloid causes dementia or is associated with it. It is intended for people with mild cognitive impairment in the hope it will arrest their functional decline. Coming after decades of disappointment, the drug’s accelerated approval should have been a cause for celebration but instead it triggered the resignation of several FDA members and widespread scepticism from experts.
Two pivotal trials involving 3,200 people showed contradictory results. One slightly slowed cognitive decline, the other showed no benefit. The data monitoring committee decided to stop the trial early, one-third of the participants discontinued and 40% experienced brain swelling and bleeding, leading to nausea, dizziness, headaches, delirium and confusion, all potentially serious symptoms in the elderly.
Statisticians stated the lack of compelling evidence in the drug’s favour and dementia experts who participated in the trial were unconvinced.
Three members of the FDA advisory panel resigned, one branding it the “worst drug approval decision in recent US history”.
The FDA conceded there were “residual uncertainties regarding clinical benefit”. Nonetheless, the drug was approved at the cost of USD$56,000 per year.
Patients who receive it will require frequent scans and symptom monitoring as well as monthly travel to an infusion centre, which itself can be a disorienting event in dementia.
Although the trial was conducted on people with early dementia, a specific cohort, the approval label does not specify this. If the required post-marketing trials do not show benefit, the FDA can – but doesn’t have to – rescind approval. Experts say such trials are even harder to conduct because patients who can obtain the drug are reluctant to take a placebo.
Advocates point out that breakthroughs ride on the shoulders of lesser therapies and this approval primes the field for better candidates to ameliorate the burden of dementia. One can only hope this is true; meanwhile, it is the lament of a neurologist (and principal investigator) that will resonate with every hassled clinician.
“I presented the data to the patient and her husband, and they didn’t hear a word I said about my concerns. All they heard was there might be benefit.” One can just about hear every clinician saying amen to that.
Frontline medicine in the modern era can be exciting and fulfilling but increasingly, it comes with the responsibility of gatekeeping. Clinicians regularly encounter drugs that are more noteworthy for their hype than efficacy but patients who read the headlines disregard the nuances and assume there must be a strong reason for regulatory approval. And since it is much easier to prescribe a drug than really talk to a patient, futile treatments propagate.
Recently, Australian clinicians had their own reason to protest the Australian Therapeutic Goods Administration (TGA) approval of a herbal remedy for benign prostate enlargement, which leads to inconvenient urinary symptoms.
The “TGA-assessed” symbol on complementary therapies is meant to inform consumers that the body has assessed the product’s health claims and found them supported by scientific evidence, which could be a positive initiative.
However, the company behind the herbal remedy funded an unblinded trial of less than 60 men, of which only 32 took the medicine, making it difficult to conclude that the drug makes a significant difference to nocturnal urination, as the company claims. Absence of the raw data means the claim cannot be verified and the TGA has not made further information publicly available.
Interestingly, complementary medicine sponsors self-certify regulatory compliance, which means they can state they hold evidence for their claims. But most products evaluated have consistently been found non-compliant because companies could not furnish the evidence.
The complementary medicine industry, with scant evidence of efficacy, is worth over AUD $5 billion a year. One might argue that adding yet another herbal concoction to the crowded market doesn’t really matter, but to do so with the TGA’s stamp does. Approving a questionable complementary medicine for a condition that has available prescription-based therapies can affect confidence in other decisions.
Whether the problem is dementia, cancer or benign prostate enlargement, patients deserve transparency that the drugs they increasingly read about and demand have been approved based on evidence. Professional societies can help by rating the strength of that evidence as strong or weak, and by defining the context of prescribing. Patients can help themselves by learning to ask questions that go beyond the headlines and probe the benefits and harms specific to their own situation.
Regulatory agencies and professional societies are powerful bodies but with great power comes great responsibility. Patients should have high expectations when their safety and wellbeing depends on which drugs are approved for general use.
Ranjana Srivastava is an Australian oncologist, award-winning author and Fulbright scholar.